Review

Current Evidence for Stereotactic Body Radiotherapy inLung Metastases

Enrique Gutiérrez 1,2, Irving Sánchez 3 , Omar Díaz 3, Adrián Valles 3, Ricardo Balderrama 3, Jesús Fuentes 3 ,Brenda Lara 3, Cipatli Olimón 3, Víctor Ruiz 3, José Rodríguez 3, Luis H. Bayardo 3, Matthew Chan 1,2,Conrad J. Villafuerte 1,2, Jerusha Padayachee 1,2 and Alexander Sun 1,2,*

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Citation: Gutiérrez, E.; Sánchez, I.;

Díaz, O.; Valles, A.; Balderrama, R.;

Fuentes, J.; Lara, B.; Olimón, C.; Ruiz,

V.; Rodríguez, J.; et al. Current

Evidence for Stereotactic Body

Radiotherapy in Lung Metastases.

Curr. Oncol. 2021, 28, 2560–2578.

https://doi.org/10.3390/

curroncol28040233

Received: 5 May 2021

Accepted: 6 July 2021

Published: 15 July 2021

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1 Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network,Toronto, ON M5G2M9, Canada; Enrique.Gutierrez@rmp.uhn.ca (E.G.); matthew.chan@bccancer.bc.ca (M.C.);Conrad.Villafuerte@rmp.uhn.ca (C.J.V.); Jerusha.Padayachee@rmp.uhn.ca (J.P.)

2 Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada3 Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social

Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico;irvingsanchez.md@gmail.com (I.S.); omardiazcazares@gmail.com (O.D.); advaqui@hotmail.com (A.V.);ricardoivan.balderrama@gmail.com (R.B.); drfuentes@protonmail.com (J.F.);brendalara912@hotmail.com (B.L.); drolimon@hotmail.com (C.O.); victormjrp5@gmail.com (V.R.);Jose_2906@hotmail.com (J.R.); luis.bayardo@imss.gob.mx (L.H.B.)

* Correspondence: Alex.Sun@rmp.uhn.ca; Tel.: +1-41-6946-2853

Abstract: Lung metastases are the second most common malignant neoplasms of the lung. It is esti-mated that 20–54% of cancer patients have lung metastases at some point during their disease course,and at least 50% of cancer-related deaths occur at this stage. Lung metastases are widely accepted tobe oligometastatic when five lesions or less occur separately in up to three organs. Stereotactic bodyradiation therapy (SBRT) is a noninvasive, safe, and effective treatment for metastatic lung diseasein carefully selected patients. There is no current consensus on the ideal dose and fractionation forSBRT in lung metastases, and it is the subject of study in ongoing clinical trials, which examinesdifferent locations in the lung (central and peripheral). This review discusses current indications,fractionations, challenges, and technical requirements for lung SBRT.

Keywords: lung SBRT; oligometastatic disease; lung cancer; lung metastases

1. Introduction

Historically the standard treatment for metastatic disease has been with systemictherapy alone. However, more recent evidence from the retrospective and prospectiveseries indicates improved long-term results when patients are managed with the additionof aggressive local treatments [1–9]

Lung metastases develop in 20–54% of cancer patients at some point in their dis-ease [10]. At least 50% of cancer-related deaths occur at this stage. Budczies et al. conducteda cohort study in 1008 postmortem patients, and the lung was the third most frequent site ofmetastases of 16 types of solid cancer [11]. Some authors consider it to be the second mostfrequent site [10,11] of metastatic target for neoplastic cells since it has a microenvironmentthat is rich in vascular supply, as well as containing small capillaries with a very shortdistance to the intravascular space [12]. In 1889, Paget proposed that metastatic diseasedoes not progress randomly but in a process that has recently been termed the metastaticcascade [12]. This process includes the steps of angiogenesis, intravasation, survival incirculation, extravasation, establishment, and growth [13,14].

Cancer cells migrate towards higher-oxygen areas, which can be achieved through theepithelial-mesenchymal transition, orientation, interaction within the stroma, and evasionof the immune system [13].

Curr. Oncol. 2021, 28, 2560–2578. https://doi.org/10.3390/curroncol28040233 https://www.mdpi.com/journal/curroncol

Curr. Oncol. 2021, 28 2561

As the tumor grows, physical barriers, such as the basement membrane and inter-stitial connective tissue, must degrade for tumor invasion to occur. Proteolytic enzymes(e.g., collagenase, trypsin, plasmin, and cathepsin B) and matrix metalloprotease expressedin tumor cells facilitate tumor spread by denaturalizing the extracellular matrix, migration,and chemotaxis, also called intravasation [10]. Hematogenic spread occurs mainly throughthe venous drainage system and the pulmonary arteries (but is less common throughthe bronchial arteries) [13]. Lymphatic spread and tracheobronchial spread are unusual,accounting for 2–5% of pulmonary metastases, and direct extension is the least commonpathway of all [10].

Finally, the proliferation of metastatic foci is succeeded by the production of proan-giogenic factors such as vascular endothelial growth factor, fibroblast growth factor, andinterleukin-8 (IL-8) [14].

2. Definition of Oligometastatic Disease

The term oligometastasis first appeared in 1995 and defines a state between localizedand widely disseminated disease [15,16]. This concept was consolidated by integrating theelements of the size and number of lesions that occur synchronously (at diagnosis of theprimary tumor or up to 3 months later) or after treatment [17,18]. An oligometastaticstatus indicates the candidacy for radical treatment for both primary and metastatictumors [7,19,20].

Another scenario in which the benefit of treatment is being analyzed is oligoprogres-sion, a state where only a limited number of metastases progress, while the rest remainstable or respond to systemic treatment [19,21]. The treatment options are to changesystemic therapy, continue with a given same scheme (in minimal progression) or de-lay changing the systemic therapy by adding local treatment, such as stereotactic bodyradiation therapy (SBRT) [19,21].

3. Number of Metastases

Oligometastatic disease (OMD) has been defined as having up to five lesions occurringseparately and distributed in up to three organs [22]. There is no standardized definition,but the SABR-COMET protocol adopts this definition for its inclusion criteria, indicatingalso that the maximum number of metastases per organ must be equal to or less thanthree lesions [23]. Multiple retrospective studies have also used a cut-off point of fivelesions [7,24–27], including patients with extrathoracic metastasis, who were candidatesfor the treatment with radical intent [24,25]. However, other studies, including ongoingstudies have included up to 10 lesions [28]. Schanne et al. analyzed patients with Non-small cell lung cancer (NSCLC) and oligometastatic disease across 54 studies where 90.5%of patients had a single metastatic lesion. Most studies have described in different waysthe term OMD as it has been defined with significant variation regarding the size and thenumber of lesions [22]. Therefore, the term OMD continues to be defined. Although thenumber of metastatic lesions included has varied among different protocols, most trialshave identified three or fewer metastases. Consequently, this number could serve as acut-off point that guides radical management in OMD in the future [5,23,27,29].

Yamamoto et al. concluded that patients with more than five lesions could be treated,as long as dose constraints are achieved. However, in that study, most patients (74%) hada unique lesion [27]. Another critical factor is lesion size. Rusthoven et al. used a cut-offpoint of 7 cm per lesion [30] and Salame et al. included patients with lesions up to 10 cm or500 cm3 [26].

4. Diagnosis and Imaging of Lung MetastasesImaging Studies

A chest X-ray is a low-sensitivity tool that cannot detect lesions of less than 1 cm [31].In patients with extrathoracic cancer, detection of a new nodule on an X-ray has a 25%probability of indicating a metastatic lesion [32].

Curr. Oncol. 2021, 28 2562

Chest computed tomography (CT) with slices of 1–1.25 mm is the preferred approachfor assessing lungs to evaluate and determine the size of the lesion [27]. The characteristicsof a metastatic lesion are widely variable. A new nodule > 10 mm has a 15% chance ofmalignancy, as shown in Figure 1. However, regardless of its size, an extrathoracic primarywith a new lung lesion is highly suggestive of metastases. Malignant lesions commonlyoccur with spiculated and irregular margins. However, metastases should not be ruled outif the lesions are rounded and smooth [33].

Curr. Oncol. 2021, 28, FOR PEER REVIEW 3

4. Diagnosis and Imaging of Lung Metastases Imaging Studies

A chest X-ray is a low-sensitivity tool that cannot detect lesions of less than 1 cm [31]. In patients with extrathoracic cancer, detection of a new nodule on an X-ray has a 25% probability of indicating a metastatic lesion [32].

Chest computed tomography (CT) with slices of 1–1.25 mm is the preferred approach for assessing lungs to evaluate and determine the size of the lesion [27]. The characteristics of a metastatic lesion are widely variable. A new nodule > 10 mm has a 15% chance of malignancy, as shown in Figure 1. However, regardless of its size, an extrathoracic pri-mary with a new lung lesion is highly suggestive of metastases. Malignant lesions com-monly occur with spiculated and irregular margins. However, metastases should not be ruled out if the lesions are rounded and smooth [33].

(a) (b)

Figure 1. CT of the chest (a) coronal view and (b) axial view showing a nodule in the right lower lobe measuring 1.5 cm, lobulated and cavitated. The lesion was biopsied and revealed an adenocarcinoma with cytomorphology and an im-munoprofile that was consistent with a colorectal primary.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a highly sensitive approach for the detection of malignant lesions with solid characteristics and larger than 8 mm, showing a sensitivity of 89% (95% CI, 86–91%) and a specificity of 75% (95% CI, 71–79%) [34]. The capacity of FDG-PET to detect pulmonary metastases and its relation to the treatment results of lung SBRT can be characterized by SUVmax, SUVmedian, and meta-bolic tumor volume (MTV). In a study by Mazzola et al., prior to the SBRT treatment, the mean SUVmax was 6.5 (range 4–17), the mean SUVmedian was 3.7 (range 2.5–6.5), and the mean MTV was 2.3 (range 0.2–31) cm3. A SUVmax < 5 and a SUVmedian < 3.5 were associated with a full response at 6 months [35]. Among patients who underwent metas-tasectomy, those with SUVmax > 4.5 (51.6% vs. 74.0%) had a decreased 5-year overall sur-vival [36]. According to Mayo Clinic and Department of Veterans Affairs (VA) models, another relevant tool is the pre-test probability of malignancy based on clinical character-istics and radiographic findings (age, smoking history, history of extrathoracic cancer, the diameter of the nodule in mm, and localization within the upper lobe) [37]. If PET-scan results are negative and the pre-test probability is equal to or greater than 65%, a needle-biopsy or video-assisted thoracic surgery should be considered [38]. In patients with an indeterminate solitary pulmonary nodule (SPN) > 8–10 mm in diameter, a biopsy is rec-ommended in the following situations: (1) Pre-test probability and radiographic findings are discordant, (2) benign diagnosis is suspected, and (3) when a fully informed patient desires proof of a malignant diagnosis before surgery, especially when the risk for surgical complications is high [39].

Figure 1. CT of the chest (a) coronal view and (b) axial view showing a nodule in the right lower lobe measuring1.5 cm, lobulated and cavitated. The lesion was biopsied and revealed an adenocarcinoma with cytomorphology and animmunoprofile that was consistent with a colorectal primary.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a highly sensitiveapproach for the detection of malignant lesions with solid characteristics and larger than8 mm, showing a sensitivity of 89% (95% CI, 86–91%) and a specificity of 75% (95% CI,71–79%) [34]. The capacity of FDG-PET to detect pulmonary metastases and its relationto the treatment results of lung SBRT can be characterized by SUVmax, SUVmedian, andmetabolic tumor volume (MTV). In a study by Mazzola et al., prior to the SBRT treatment,the mean SUVmax was 6.5 (range 4–17), the mean SUVmedian was 3.7 (range 2.5–6.5), andthe mean MTV was 2.3 (range 0.2–31) cm3. A SUVmax < 5 and a SUVmedian < 3.5 wereassociated with a full response at 6 months [35]. Among patients who underwent metas-tasectomy, those with SUVmax > 4.5 (51.6% vs. 74.0%) had a decreased 5-year overallsurvival [36]. According to Mayo Clinic and Department of Veterans Affairs (VA) models,another relevant tool is the pre-test probability of malignancy based on clinical charac-teristics and radiographic findings (age, smoking history, history of extrathoracic cancer,the diameter of the nodule in mm, and localization within the upper lobe) [37]. If PET-scan results are negative and the pre-test probability is equal to or greater than 65%, aneedle-biopsy or video-assisted thoracic surgery should be considered [38]. In patientswith an indeterminate solitary pulmonary nodule (SPN) > 8–10 mm in diameter, a biopsy isrecommended in the following situations: (1) Pre-test probability and radiographic findingsare discordant, (2) benign diagnosis is suspected, and (3) when a fully informed patientdesires proof of a malignant diagnosis before surgery, especially when the risk for surgicalcomplications is high [39].

The possibility of technical artifacts should be taken into account. Catheters, metallicprostheses, and other devices can show more FDG uptake and overestimate affected areas.Another possible artifact is one generated by different respiratory phases when PET iscombined with CT, being the most common site of discrepancy the lung–diaphragm limits,potentially confusing the avid areas of FDG of the liver with lung lesions [40].

Curr. Oncol. 2021, 28 2563

Another alternative under evaluation is the use of liquid biopsies from blood samples,where nucleic acids from tumor cells can be identified [18]. Lebofsky et al. analyzedpatients with recurrent/metastatic cancer and failure of standard therapy, a biopsy wascompared to circulating tumor DNA determination, and a 97% match was achieved [41].

5. Stereotactic Body Radiation Therapy for the Lung

Stereotactic body radiation therapy (SBRT) is a noninvasive cancer treatment that useshigh doses of precise radiation to extracranial target sites [42]. The American Associationof Physicists in Medicine (AAPM) defines SBRT as a stereotactic treatment that deliversa high dose of radiation within a short cycle, generally limited to less than or equal tofive fractions with a dose of 6 to 34 Gy per fraction [43,44]. Outside the United States,SBRT has been accepted as a highly conformal technique with regimens including up to10 fractions with a biologically effective dose (BED) ≥ 100 Gy10 or doses at least biologicallyequivalent to a radical course of treatment when given over a protracted conventionally(1.8–3 Gy/fraction) fractionated schedule [43,45–47].

However, groups in several countries (AAPM, ASTRO, ACR, CARO-SBRT, and theNRIG) agree on the following points: SBRT is an external beam radiotherapy method thataccurately delivers a high dose of radiation in one or a few fractions, to an extracranialtarget, which results in an increased effective biological dose [45,47].

Radiobiological Principles of SBRT

The loss of reproductive ability due to the creation of double-stranded breaks in DNAis the primary mechanism by which conventional irradiation kills a cell: Any cell that isunable to reproduce indefinitely is considered to be dead by definition, although it mayremain metabolically active for some time [48,49].

Five critical factors determine the effects of radiotherapy on tumors:

1. Repair of sublethal cell damage;2. Cell repopulation followed by radiation;3. Cell redistribution in the cell cycle;4. Re-oxygenation of surviving cells;5. Radiosensitivity (intrinsic) [48,49].

If a given dose of radiotherapy is divided into daily fractions according to a conven-tional scheme, redistribution and re-oxygenation facilitate the increase in cell death byredistributing resistant survivors into more radiosensitive phases over time. However, cellrepair and repopulation produce increased numbers of surviving cells due to cell recoveryand repopulation between doses [48].

Following radiation, three phases of histopathologic change in the lungs have been de-scribed. The early/latent phase occurs within a month after radiation and is characterizedby the loss of type I alveolar epithelial cells (AEC), alveolar transudates, interstitial edema,and type II AEC morphologic changes. The acute exudative phase (radiation pneumonitis)occurs between three weeks and up to 6 months after radiation. This phase presentsfibrin-rich exudates, interstitial edema, and accumulation of alveolar macrophages. Thelate or fibrotic phase begins approximately 6 months after radiation and is defined by aconstant loss of type I AEC, capillary loss, and progressive collagen deposition [50].

For SBRT, there were initial queries on whether the mechanism of action of the killingof tumor cells is similar to conventional radiotherapy. Several studies have shown that theradiobiology of SBRT is quite different [51–54].

The influence of the five Rs on the treatment outcome is modified with the use of SBRT.Due to the shorter treatment time and decreased number of fractions, tumor repopulationand redistribution effects are diminished [52,55]. The steep dose gradients lessen the impactof normal organ sparing [47,52]. Reoxygenation and radiosensitivity remain as factors.However, acute hypoxia and fast reoxygenation are more commonly observed with SBRTcompared to chronic hypoxia and slow reoxygenation [52,56–58].

Curr. Oncol. 2021, 28 2564

Tumor cell death from SBRT can be a result of the combination of direct tumorcell eradication and indirect tumor cell killing secondary to vascular or endothelialdamage [51,52,54,59,60]. Vascular damage could indirectly lead to tumor death for tworeasons. SBRT can abruptly cut off blood supply and can induce endothelial apoptosis,which can heighten tumor radiosensitivity [54,61,62].

Numerous reports have described that vascular tumor damage as tumor volume de-creases after being irradiated with a dose higher than 10 Gy in a single event. The vasculartumor structures become disorganized and fragmented [51,53]. Endothelial tumor cells dieas a result of direct radiation damage, vascular permeability, and plasma extravasation,causing erythrocyte concentration within the narrow capillaries, leading to retardation,blood stasis, and vascular collapse [53].

Immune reactions and death of cancer stem cells are also thought to contribute toSBRT radiobiology [52–54]. It has been suggested that SBRT also provokes an immunereaction by increasing T-cell, leading to reduction of the primary tumor cells or distantmetastases in a CD8+ T-cell dependent fashion [51].

Cancer stem cells are described as being perivascular. They are considered to bea possible cause of radioresistance in conventional radiotherapy as they are able to re-proliferate even after irradiation. SBRT is thought to be able to eradicate these stem cells,thereby decreasing the chances of recurrence [53,54].

6. Eligible Patients

Pulmonary comorbidity is the most common reason for inoperability. Patients whoare considered medically inoperable are defined based on poor lung function evaluated bya thoracic surgeon or respirologist and encompassing the following parameters: Predictedforced expiratory volume in 1 s (FEV1) < 40%, predicted postoperative FEV1 < 30%, baselinehypoxemia (≤70 mmHg) and/or hypercapnia (>50 mmHg), predicted reduced diffusingcapacity < 40% and predicted consumption during exercise < 50% [63,64]. Poor lungfunction by itself is not a contraindication for SBRT. There is no lower limit of lung functionprior to SBRT treatment and may even be offered for patients with extreme pulmonarycomorbidities [65].

Inoperability also encompasses serious comorbidities such as severe pulmonary hy-pertension; diabetes mellitus with end organ damage; cerebral vascular disease; severechronic heart disease or severe cardiovascular disease [41,66,67] SBRT is recommended asa treatment option for this population if they have an estimated life expectancy greaterthan 1 year [68].

Additional criteria for eligibility include refusing surgical intervention [41,69], recur-rent or metastatic lung lesions [69], Eastern Cooperative Oncology Group score ≤ 3 [67,68]or controlled primary [24,69]. There is no contraindication in terms of age [68,70] (seeTable 1).

Table 1. Patient eligibility criteria for SBRT.

Age Any

ECOG 0–2Medically operable patients Patients who refuse surgical intervention

Number of lesions Range 1–5Tumor diameter <50 mm

Location PeripheralCentral

Curr. Oncol. 2021, 28 2565

Table 1. Cont.

Age Any

Medically inoperable patients

Poor lung function:FEV1 < 40% predicted,

postoperative FEV1 < 30% predicted,decrease diffusing capacity < 40% predicted,baseline hypoxemia (≤70 mm Hg) and/or

hypercapnia (>50 mmHg), and oxygenconsumption during exercise < 50% predicted.Important comorbidities: Severe pulmonary

hypertension; diabetes mellitus withend-organ damage; severe cerebral,

cardiovascular or peripheral vascular disease;or severe chronic heart disease

ECOG: Eastern. Operative Oncology Group Scale of performance status. FEV1: Forced Expiratory Volume in thefirst second.

6.1. Considerations of the Number and Size of Metastases

In May 2020, Bernard et al. reported the case of a patient with five metastatic lunglesions that were treated synchronously with SBRT, followed by two additional lesions alsotreated synchronously with SBRT, for a total of seven lesions in the same lung, separatedby less than 5 cm. After a 14-month follow-up, the authors found no progression and nosignificant late side effects [71].

In relation to the size of treatable lesions, a study by the German Society for RadioOncology (DEGRO) established a consensual limit of lung tumor size for SBRT of 4 to 5 cm,with a more fractionated regimen for larger tumors [72].

In one of the largest series of metastatic lung tumors treated with SBRT, the experienceof the RSSearch® Patient Registry, the median number of metastases was 1 (1 to 3), with amean volume of 10.58 cc (0.1 to 654.5 cc). The mean overall survival for the entire group was26 months. The overall survival at 1, 3, and 5 years was 74.1%, 33.3%, and 21.8% of patients,respectively. The mean local control (LC) for the group was 53 months. The LC rate at 1, 3,and 5 years was 80.4%, 58.9%, and 46.2%, respectively. A statistically significant differencewas identified, with improvement in local control for minor tumors. Local control at 2 yearswas 72.9%, 64.2%, and 45.6% for tumor volume <11 cc, 11–27 cc, and >27 cc, respectively(p = 0.0005 by the log-rank test; p = 0.0011 by the Gehan-Breslow-Wilcoxon test). Thistranslated into an improvement in OS, with a 2-year OS of 62.4%, 60.9%, and 46.1% fortumors with volumes of <11 cc, 11–27 cc, and >27 cc, respectively, and the mean OS forlesions <11 cc, 11–27 cc, and >27 cc was 29, 31, and 21 months, respectively (p = 0.0023 bythe log-rank test; p = 0.0011 by the Gehan-Breslow-Wilcoxon test) [70].

The ASTRO 2017 evidence-based guideline for NSCLC established that SBRT is anappropriate option for tumors > 5 cm in diameter within an acceptable therapeutic range.However, this applies to primary lung tumors, with conditional strength of recommenda-tion and a low quality of evidence [42].

Few results have been produced specifically for the use of SBRT in larger lung tu-mors [73].

6.2. Peripheral and Central Lesions: Technical, Fractional, and Dose Prescription Differences

Traditionally, only patients with tumors at least 2 cm away from the bronchial tree havebeen considered for SBRT, following a commonly used three to four fraction regimen [15](Figure 2). However, at present, patients with central tumors, defined as those where theclosest point is within 2 cm proximal to (but not contacting or abutting) the main bronchialtree or within 2 cm (contacting or not) of mediastinal structures [74,75], are at higher riskfor toxicity when treated with SBRT, compared to patients with peripheral tumors [34],avoiding the use of a three-fraction regimen is recommended in this scenario [42]. Tumors

Curr. Oncol. 2021, 28 2566

with the highest risk for SBRT are those with an ultra-central location, defined as anyGTV at ≤1 cm from the proximal bronchial tree that overlaps the trachea or the mainbronchus [75] or tumors that contact (abut) the proximal bronchial tree [74,75]. High ratesof toxicity and death are associated with treatment in this situation, increasing the interestin identifying an optimal, effective, and safe dose for this group of patients [76].

Curr. Oncol. 2021, 28, FOR PEER REVIEW 7

Tumors with the highest risk for SBRT are those with an ultra-central location, defined as any GTV at ≤ 1 cm from the proximal bronchial tree that overlaps the trachea or the main bronchus [75] or tumors that contact (abut) the proximal bronchial tree [74,75]. High rates of toxicity and death are associated with treatment in this situation, increasing the interest in identifying an optimal, effective, and safe dose for this group of patients [76].

Figure 2. Treatment-planning dose for lung SBRT in a patient with biopsy-proven metastatic breast cancer, prescribing 48 Gy in four fractions. Isodose lines: Burgundy, 24 Gy; light orange, 44 Gy; and blue, 48 Gy.

To reduce the probability of these complications, Bral et al. proposed a treatment with adapted risk fractions, increasing the number of fractions to the range of five to eight and with doses per fraction of 4–8 Gy, which have shown acceptable toxicity [77].

For central tumors in which SBRT is considered very high risk, hypofractionated ra-diotherapy using 6–15 fractions can be considered, transposing what is established by the ASTRO guideline for NSCLC in the early stages [42].

Timmerman et al. reported high rates of toxicity associated with central tumors com-pared to peripheral ones in the definitive treatment setting for patients with NSCLC [76]. Likewise, Lischalk et al. demonstrated a rate of local control of 57.4% at 2 years, signifi-cantly lower than that reported by Timmerman (95%) [78].

More recent retrospective data that include heterogeneous dose and fractionation schedules seem to indicate that the risk for irradiation in the central regions may not have the significant impact postulated by Timmerman et al. [76,78,79]. Chaudhuri et al. ob-served that this group of central tumors (including primary NSCLC and lung metastases) exhibited excellent tumor control and a similar toxicity rate to its less central counterpart, suggesting that even ultra-central tumors can be treated with 50 Gy in four or five frac-tions if not in contact with the esophagus [80].

The fractionation of 50 Gy in five fractions was described by Bezjak et al. in the con-text of early-stage NSCLC, reporting reasonable control rates and acceptable toxicities [81]. In this context, the NRG-BR001 clinical trial was designed, which is currently evalu-ating prescribed doses for lung metastases of 45 Gy in three fractions for peripheral lesions and 50 Gy in five fractions for central lesions. The successful completion of this trial will provide valuable information for the design of new clinical trials and the development of treatment guidelines for oligometastatic disease [82].

There is no consensus at present on the ideal dose and fractionation for SBRT in lung metastases [78,80]. A brief summary of published studies regarding differences in dose and fractionation for SBRT for lung metastases according to central or peripheral location is depicted in Table 2.

Figure 2. Treatment-planning dose for lung SBRT in a patient with biopsy-proven metastatic breastcancer, prescribing 48 Gy in four fractions. Isodose lines: Burgundy, 24 Gy; light orange, 44 Gy; andblue, 48 Gy.

To reduce the probability of these complications, Bral et al. proposed a treatment withadapted risk fractions, increasing the number of fractions to the range of five to eight andwith doses per fraction of 4–8 Gy, which have shown acceptable toxicity [77].

For central tumors in which SBRT is considered very high risk, hypofractionatedradiotherapy using 6–15 fractions can be considered, transposing what is established bythe ASTRO guideline for NSCLC in the early stages [42].

Timmerman et al. reported high rates of toxicity associated with central tumors com-pared to peripheral ones in the definitive treatment setting for patients with NSCLC [76].Likewise, Lischalk et al. demonstrated a rate of local control of 57.4% at 2 years, significantlylower than that reported by Timmerman (95%) [78].

More recent retrospective data that include heterogeneous dose and fractionation sched-ules seem to indicate that the risk for irradiation in the central regions may not have thesignificant impact postulated by Timmerman et al. [76,78,79]. Chaudhuri et al. observedthat this group of central tumors (including primary NSCLC and lung metastases) exhibitedexcellent tumor control and a similar toxicity rate to its less central counterpart, suggesting thateven ultra-central tumors can be treated with 50 Gy in four or five fractions if not in contactwith the esophagus [80].

The fractionation of 50 Gy in five fractions was described by Bezjak et al. in the contextof early-stage NSCLC, reporting reasonable control rates and acceptable toxicities [81].In this context, the NRG-BR001 clinical trial was designed, which is currently evaluatingprescribed doses for lung metastases of 45 Gy in three fractions for peripheral lesionsand 50 Gy in five fractions for central lesions. The successful completion of this trial willprovide valuable information for the design of new clinical trials and the development oftreatment guidelines for oligometastatic disease [82].

There is no consensus at present on the ideal dose and fractionation for SBRT in lungmetastases [78,80]. A brief summary of published studies regarding differences in doseand fractionation for SBRT for lung metastases according to central or peripheral locationis depicted in Table 2.

Curr. Oncol. 2021, 28 2567

Table 2. Brief Summary of published studies of lung SBRT-treated central and central/peripheral lung metastases and differences in the prescribed dose.

Author/Year Location Technique Description Prescribed Dose Local Control Overall Survival Grade > 3 Toxicity

Milano et al.2009 [79] Central Relaxed end-expiratory

breath holding Dmean 50 Gy (30–63 Gy) most in 4–5 Gy per fx 73% at 2 yr 47% at 2 yr 5/53 pts w/grade 5

Unger et al.2010 [83] Central

CyberKnife system withsynchrony fiducial

tracking technology30–40 Gy in 5 fx 63% at 1 yr 54% at 1 yr 3/20 pts w/severe

pneumonitis

Rowe et al.2012 [84] Central 100% 4D-CT with ITV and

CBCT guidance system75% BED 100 Gy 57% 12.5 Gy × 4 fx 25% BED

<100 Gy 75% at 2 yr _______ 5/47 patients

Nuyttens et al.2012 [85] Central CyberKnife respiratory

tumor tracking system 45–60 Gy/5–6 Fx 64% at 2 yr 75% at 2 yr No grade 4–5 toxicity,17.12% grade 3

Nuyttens et al.2014 [86]

Peripheral Size >3 cmReal-time tumor tracking+ radiopaque markers

60 Gy/3 fx 90% at 2 yr 58% at 3 yrNo grade 4–5 toxicityPeripheral Size <3 cm 30 Gy/1 fx 74% at 2 yr

Central 60 Gy/5 fx 100% at 2 yr 53% at 3 yrCentral in contact with

the esophagus ormediastinum.

56 Gy/7 fx 100% at 2 yr

Chaudhuri et al.2015 [80]

Central 50% IMRT/4D-CT/PETrespiratory gating

(78%) 50 Gy/4 fx; (22%) 50.4 Gy/5 fx.Proportionally, more centrally located with 5 fx.

_______ 73.8% at 2 yrNo differences regarding

tumor location

3% at 3 yrPeripheral 50% _______ 11.6% at 3 yr

Davis et al.2015 [76] Central

CyberKnife withsynchrony respiratory

motion tracking system

Dmean 37.5 Gy (16–60 Gy) in 1–5 fx (media3 fx), Dmean BED 93.6 Gy 69.8% at 2 yr 49.5% at 2 yr No grade 3–5 toxicity

Haseltine et al.2015 [87] Central 4D-CT with ITV and

CBCT guidance system 36–60 Gy in 2–5 fx, 56% received 45 Gy in 5 fx 77.4% at 2 yr 63.9% at 2 yr 12%, four patientswith grade 5

Lischalk et al.2016 [78] Central

Synchrony respiratorymotion tracking systemwith fiducial markers

35–40 Gy/5 fx BED 59.5–72 Gy

57.4% at 2 yrNo differencesregarding the

prescribeddose

40% at 2 yrNo differences regarding

the prescribed dose

15% (one patientwith grade 4)

Lindberg et al.2017 [88]

Central ≤1 cm fromthe proximal bronchial

tree_______ 56 Gy/8 fx _______ _______ 28% grade 3–5

ITV: Internal target volume; Dmean: Mean dose; BED: Biologically equivalent dose; Gy: Gray; fx: Fractions; and yr: Years.

Curr. Oncol. 2021, 28 2568

7. Treatment Volumes

The gross tumor volume (GTV) represents the solid tumor and ground glass densityin each axial CT slice using a lung window (this value can be based on FDG-PET ifavailable) [4,24,68]. An expansion from the GTV to the clinical target volume (CTV)margin is not routinely added for lung SBRT practice. Thus, the CTV margin is commonly0 mm [63,64]. Grills et al. conducted a Phase II study, called Trial in Stereotactic LungRadiotherapy, and used a 4 mm expansion (3–5 mm) of the GTV-ITV to create the CTV [65].

The creation of an internal target volume (ITV) is mandatory in this scenario [4,66,68].The ITV can be created from an eight-phase 4D tomography acquired in a normal

respiratory cycle. The GTV is outlined in a free-breathing scan, and it is expanded infour inspiratory and four expiratory phases. When the breath-hold technique is used, ITVcreation is not mandatory, as it is significantly reduced compared to the free-breathingphase [4,24,66,68]. Finally, the planning target volume (PTV) is created by an isotropicgrowth of 5 mm from the ITV (range 3–7 mm) [4,24,66,68].

8. Treatment Dose

A dose and fractionation with BED of at least 100 Gy should be used [68]. Accordingto the consensus of the ESTRO ACROP, the selection of a scheme depends upon the locationand size of the tumor [68]. (see Table 3).

Table 3. SBRT doses and fractionations for lung lesions according to the ESTRO ACROP consensuson the implementation and practice of SBRT for peripheral lesions in early-stage non-small-celllung cancer.

Tumor Location Dose to PTV BED10 of the Prescribed Dose to the PTV

Peripheral 3 × 15 Gy (45 Gy) 113 Gy BED10Central 4 × 12 Gy (48 Gy) 106 Gy BED10

According to CARO, the following doses and fractionations can be used for primaryand metastatic lung lesions [44]. (see Table 4).

Table 4. CARO clinical practice guidelines for lung SBRT.

Prescribed Dose for PTV BED10 of the Prescribed Dose to the PTV

8 × 7.5 Gy (60 Gy) 105 Gy BED105 × 10 Gy (50 Gy) 100 Gy BED104 × 12 Gy (48 Gy) 106 Gy BED10

3 × 18–20 Gy (54–60 Gy) 151–180 Gy BED101 × 34 Gy (34 Gy) 150 Gy BED10

9. Technical Requirements

The main technical requirements for SBRT include:

1. Modern linear accelerators to enable image-guided radiation therapy (IGRT) andmotion-management systems;

2. Sophisticated immobilization devices [44,89];3. Quality controls [72].

9.1. Simulation

Two critical issues in the simulation of pulmonary SBRT are the immobilization andevaluation of tumor movement [64]. Patients are normally positioned supine with theirarms overhead, in a custom immobilization device [90], such as a vacuum-sealed foam bag,a stereotactic frame with a wing board and an alpha-cradle, and an immobilizer for the feetand knees [91].

Curr. Oncol. 2021, 28 2569

The images required for simulation and planning may include detailed 4D-CT motionestimation, as well as additional soft tissue (MRI) or metabolic (PET) information [92,93].The latter is particularly useful for tumors that are not well-defined or close to the chestwall [44].

The standard imaging modality for targeting lung tumors and organs at risk (OAR)contouring is tomography, with a maximum thickness per slice of < 3 mm, which mustcompletely include both lungs [45,94] and at least one individual evaluation of the move-ment of the lungs using 4D-CT. Where this technology is lacking, the tumor movement canbe determined by fluoroscopy or scanning in inspiration and expiration [45].

9.2. Pretreatment Setup and Treatment Delivery9.2.1. IGRT and Motion Management Systems

The available image-guided radiation therapy (IGRT) and motion management tech-niques are classified into three domains: Kilovoltage (kV) images, megavoltage (MV)images, and optical images [91].

Conventional kV-imagers can be fluoroscopic imaging devices, retractable kV sources,detector panels, mounted X-ray imagers, and floor detectors that provide flat radiographicimages of the patient. The 3D-CT with cone-beam (3D-CBCT) shows the internal anatomyof the patient before each fraction, allowing the visualization of a range of geometricdeviations, such as uncertainties due to movement [91,94]. However, for lung images, therespiratory-phase projections are averaged to reconstruct a single 3D scan, leaving blurredregions of interest or multiple diaphragmatic artifacts that give incorrect information onthe tumor amplitude and its position relative to the OARs during breathing. The use of4D-CT, by contrast, allows respiratory movement to be considered [91,95].

The 4D-CBCT provides complementary information on the interfraction trajectoryof the tumor that 3D-CBCT cannot, ensuring that the margins around the target are keptsmall, reducing their inter-observer variability for patient positionin [15]. MV images canbe obtained using electronic portal imaging devices, fan beam MV-CT with tomotherapy,MV-CBCT, and providing 3D images before treatment as a quick and accessible tool toreplace dosimetry and verification of modulated deliveries [91].

Repositioning the treatment couch is another important pretreatment intervention.The patient can be positioned and aligned according to markings, tattoos or immobilizationdevices. After imaging, matching the patient’s current position against established land-marks is mandatory, and this can be achieved using either a couch with three translationsand one rotation on the anteroposterior axis or one with 6 degrees of freedom, if available.The latter option allows for two extra rotations in the posteroanterior and lateral axes,representing clear advantages to correct positioning errors but is not mandatory for SBRTaccording to the available guidelines [91,96,97].

Typical strategies for managing respiratory movement include deep inspiration breath-hold during treatment, through active control of breathing, abdominal compression, andother mechanical means. Alternatively, radiation can be delivered at specific phases ofthe respiratory cycle using a respiratory-gated system [91,98]. Another device for thecontinuous administration of positive air pressure is being tested for its potential use inpulmonary radiotherapy [91,99].

These techniques are adopted to support the treatment in real time, either by movingthe full linear accelerator, tilting the gantry, repositioning the patient with a robotic couchor changing the position and shape of the treatment beam with a multi-leaf collimator [95].The most advanced motion-management technique, which is not based on images, is thatof electromagnetic transponders [91,99]. Tumor tracking can also be performed using directimaging monitoring (fluoroscopy, slow CT or 4D-CT), which is frequently associated withfiducial markers [64,100] or by the evaluation of the chest wall [101].

Curr. Oncol. 2021, 28 2570

9.2.2. Sophisticated Immobilization Devices

A wide variety of immobilization devices exist, from stereotactic body frames toalpha cradles, vacuum bags, foot, and knee supports, and abdominal compressors [44].The choice of which to use depends upon the experience with each and availability at agiven institution.

9.2.3. Quality Control

To carry out adequate quality control, the following is required: Small-field dosimetryfor commissioning with corresponding detectors (e.g., microchamber) [102]; system-specificend-to-end tests for both static and moving target volumes, especially if a respiratory man-agement system is being used [103]; periodic verification of geometric and dosimetricaccuracy according to system-specific guidelines; and daily quality control of the consis-tency of the stereotactic frame and/or the isocenter image guide system with the isocentertreatment beam. The dosimetric precision must be a maximum of 3% from a target volumeof more than or equal to 2 cc with homogeneous phantoms. For target volumes smallerthan 2 cc, the measurement uncertainties may be greater than the desired dosimetricprecision [72].

The lung dose constraints suggested by the American Association of Physicists inMedicine (AAPM) are V7 < 1500 cc for one fraction, V11.6 < 1500 cc for three fractions(2.9 Gy/fraction), and V12.5 Gy > 1500 cc for five fractions (2.5 Gy/fraction) to an end-point grade 3 toxicity for basic lung function and V7.4 Gy < 100 cc for one fraction,V12.4 < 1000 cc for three fractions (3.1 Gy/fraction), and V13.5 < 1000 cc for five fractionsfor pneumonitis [43]. The Japan Clinical Oncology Group (JCOG) 0403 Protocol considereddose constraints for the lung with a mean dose ≤ 18 Gy, 40 Gy irradiated volume ≤ 100 cc,V15Gy < 25%, and V20 < 20% [104]. Dunlap et al. [105] determined a dose constraint forthe chest wall of 30 Gy in three to five fractions to < 30 cm3 to decrease the risk of toxicitywithout compromising tumor coverage.

Figure 3 summarizes and describes the minimum technical requirements to carry outa SBRT protocol.

In a series of 206 patients treated with SBRT and a median follow-up of 26 months, 54%of the patients died, the median OS was 33 months, and the median PFS was 13 months.Although the median PFS survival was low at 2, 3, and 5 years (36%, 25%, and 16%,respectively), the local control was high (85%, 83%, and 81%, respectively) [106].

In another series of 219 patients with a median follow-up of 16.5 months, the medianOS was 27.6 months, freedom from distant progression (DP) at 2, 3, and 5 years (46%, 40%,and 34%, respectively) were also lower than LC at 2, 3, and 5 years (84%, 78%, and 75%,respectively) [107]. In terms of histology, Takeda et al. [6] reported worse local controlin patients with colorectal pulmonary metastases treated with SBRT compared to othertumors. Therefore, dose escalation should be considered in such cases. A retrospectivestudy conducted by Jingu et al. [108] reported a better local control rate with higher BED(≥100 Gy BED in patients prescribed with D95 or ≥ 130 Gy BED in patients prescribed withan isocenter dose) as well in patients with rectal cancer, age ≥ 70 years old, and receivingadjuvant chemotherapy after SBRT in multivariate analysis.

Curr. Oncol. 2021, 28 2571

Curr. Oncol. 2021, 28, FOR PEER REVIEW 13

Figure 3. Flow chart describing the minimum technical requirements necessary to carry out the SBRT process. Local control and overall survival.

Figure 3. Flow chart describing the minimum technical requirements necessary to carry out the SBRT process. Local control and overall survival.

Curr. Oncol. 2021, 28 2572

A retrospective study including 577 eligible patients utilizing a patient registry an-alyzed OS in 447 patients and LC in 304 patients. The median OS was 26 months, withactuarial survival at 1, 3, and 5 years of 74.1%, 33.3%, and 21.8%, respectively. The medianLC was 53 months and had rates of 80.4%, 58.9%, and 46.3%, respectively at the same inter-vals. Contrary to what was described by Sharma, colorectal primary had worse OS thanthe head and neck or breast primaries, but no differences were seen in LC [70]. Gomez et al.compared local consolidative therapy (LCT) using either radiation therapy or surgeryversus observation in patients with NSCLC who did not progress after front-line systemictherapy. This study was closed early, with only 49 patients assigned after a significantlyimproved progression-free survival (PFS) was seen in the LCT arm. The PFS benefit wasa median of 14.2 months in the intervention arm against 4.4 months in the observationarm (p = 0.022). OS had a median benefit of 24.2 months in the intervention arm comparedwith the observation arm (41.2 vs. 17 months) [29]. The SABR-COMET trial randomized99 patients (with a life expectancy of at least 6 months) to receive palliative standard ofcare or standard of care and SABR. The SABR group had a preponderance of prostatecancer patients (21%), while the control group had a preponderance of colorectal cancerpatients (27%). The median OS in the no-SABR group was 28 versus 41 months in the SABRgroup. However, there was a 20% increase in grade 2 or worse adverse events, and threepatients out of 66 in the SABR treatment group had treatment-related deaths [9]. Althoughthese two major clinical trials were not designed to evaluate the outcome of SBRT for lungmetastases, many of the patients included in these two studies were treated with SBRT forlung metastases.

10. Acute and Late Toxicity

SBRT for pulmonary metastases, is usually devoid of significant toxicities, with lessthan 5% of patients featuring acute grade 2 or higher toxicity: In regards to late toxicity,the most-reported symptom in that study was grade 2 cough (7.5%) and grade 2 fatigue(6%) [106]. In a study of 207 patients, Kessel reported a higher incidence of grade 2 toxicityand a 9.7% rate of symptomatic pneumonitis [107].

Toxicities higher than grade 2 are low, with only 2.9% presenting symptoms withinthe first 6 months and 2.5% after 1 year. In Kessel’s study, patients who reported late severedyspnea after the SBRT treatment had been diagnosed with chronic obstructive pulmonarydisease before the treatment [107].

11. Prognostic Factors

In a series of 206 patients treated with SBRT and a median follow-up of 26 months, 54%of the patients died, the median OS was 33 months, and the median PFS was 13 months.Although the median PFS survival was low at 2, 3, and 5 years (36%, 25%, and 16%,respectively), the local control was high (85%, 83%, and 81%, respectively) [106].

In another series of 219 patients with a median follow-up of 16.5 months, the medianOS was 27.6 months, and rates of distant progression (DP)-free survival at 2, 3, and 5 years(46%, 40%, and 34%, respectively) were also lower than LC at 2, 3, and 5 years (84%, 78%,and 75%, respectively) [107].

A retrospective study that included 577 eligible patients utilizing a patient registryanalyzed OS in 447 patients and LC in 304 patients. The median OS was 26 months, withactuarial survival rates at 1, 3, and 5 years of 74.1%, 33.3%, and 21.8%, respectively. Themedian LC was 53 months with rates of 80.4%, 58.9%, and 46.3%, respectively at thesame intervals. Contrary to what was described by Sharma [106], colorectal primary hadworse OS than head and neck or breast primaries, but no differences were seen in LC [70].Gomez et al. compared local consolidative therapy (LCT) using either radiation therapy orsurgery versus observation in patients with oligometastatic NSCLC who did not progressafter front-line systemic therapy. This study was closed early, with only 49 patients assignedafter significantly improved progression-free survival (PFS) was seen in the LCT arm. ThePFS benefit was a median of 14.2 months in the intervention arm against 4.4 months in the

Curr. Oncol. 2021, 28 2573

observation arm (p = 0.022). OS had a median benefit of 24.2 months in the interventionarm compared with the observation arm (41.2 vs. 17 months) [29]. The SABR-COMETtrial randomized 99 patients with oligometastatic cancer at various locations (with a lifeexpectancy of at least 6 months) to receive palliative standard of care or standard of careand SABR. The SABR group had a preponderance of prostate cancer patients (21%), whilethe control group had a preponderance of colorectal cancer patients (27%). The median OSin the no-SABR group was 28 versus 41 months in the SABR group. However, there was a20% increase in grade 2 or worse adverse events, and three patients out of 66 in the SABRtreatment group suffered treatment-related death [9].

12. Conclusions

• Lung SBRT is an external beam radiation therapy method that accurately delivers ahigh dose of radiotherapy within a limited number of fractions, often using biologicallyeffective doses ≥ 100 Gy10.

• Its use in treating lung oligometastases is becoming increasingly prevalent withevidence supporting both a clinical benefit and limited toxicity.

• There is variation in the dose-fractionation schedules used, and an optimal regimenfor central or ultracentral tumours has yet to be defined.

• The main technical requirements for SBRT include modern linear accelerators withimage-guided radiation therapy, advanced immobilization devices, motion manage-ment strategies, and quality controls.

Author Contributions: Conceptualization, E.G., I.S., O.D., A.V., A.S., J.F.; and R.B.; methodology,E.G., R.B., A.S. and J.R.; software, O.D., J.F., V.R. and B.L.; validation, A.S., J.P. and C.J.V.; formalanalysis, E.G. and A.S.; investigation, E.G., M.C., C.J.V., A.S. and L.H.B.; resources, L.H.B., C.O. andJ.F.; data curation, O.D. and C.O.; writing—original draft preparation, E.G. and I.S., A.S. writing—review and editing, E.G., I.S., A.V. and A.S.; visualization, V.R., B.L. and J.R.; supervision, E.G., I.S.and A.S.; project administration, M.C. and J.P.; funding acquisition, A.S.; All authors have read andagreed to the published version of the manuscript.

Funding: This research was funded by Elzbieta Rosnowska-Perera and Norbert Perera.

Conflicts of Interest: The authors declare no conflict of interest.

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